ABSTRACT/PROJECT SUMMARY In this project, we seek to identify novel blood-based epigenomic biomarkers to be used in early childhood as biomarkers of natural history of prenatal exposure to gestational diabetes (GDM) and for profiling risks of obesity and cardiometabolic phenotypes among children born to GDM mothers. We will leverage the largest prospective collections worldwide of biospecimens, anthropometry and laboratory data from the Tianjin GDM longitudinal observational study (TGDM-O), Tianjin, China, which have been funded by the European Foundation for the Study of Diabetes (EFSD). In Aim 1, we will identify in a longitudinal observational study blood methylomic profiles in early childhood that reflect antecedent GDM exposures. In Aim 2, we will identify in a longitudinal observational study blood methylomic profiles in early childhood that predict future obesity and dysmetabolism risk trajectories. To ensure generalizability, in Aim 3, we will confirm our findings in three large independent cohorts in the US and Europe (i.e., Project Viva, Avon Longitudinal Study of Parents and Children [ALSPAC], and Born in Bradford). This is the first study to prospectively examine the effects of GDM on the child?s methylome and metabolic health, and determine the generalizability of our findings in three independent cohorts. If successful, our project will provide accurate tools to guide childhood interventions through early biomarkers of effect. These biomarkers could be eventually used to implement personalized measures among children and enhance strategies to obesity prevention. The proposed research will generate a model that could be extended to other prenatal risk factors, as well as to other conditions with their root causes in pregnancy.